The present invention relates to new sulphoxybenzamides of formula I, 
wherein the groups R1, R2, R3, A1, A2, Z0, Z1, Z2, m and n have the meanings given in the claims and specification, processes for preparing them as well as their use as medicaments, particularly as leukotriene B4 (LTB4) antagonists.
Benzamidine derivatives are known from the prior art as active substances with valuable pharmaceutical properties. Thus, for example, International Patent Applications WO 97/21670 (corresponding to U.S. Pat. No. 6,127,423) and WO 98/11062 (corresponding to U.S. Pat. No. 6,197,824 B1) disclose inter alia benzamidines which have free hydroxy groups. They contain no references of any kind to benzamidines containing sulphate groups.
The aim of the present invention is to prepare new LTB4 antagonists which, by virtue of their LTB4 antagonistic properties, have many possible uses in the therapeutic field.
Surprisingly, it has been found that benzamidine derivatives containing sulphate groups, of general formula (I) 
wherein the groups R1, R2, R3, A1, A2, Z0, Z1, Z2, m and n have the meanings given in the claims and specification, have an LTB4 antagonistic activity and may be used according to the invention for the prevention and treatment of diseases in which LTB4 antagonists may provide a therapeutic benefit.
The invention thus relates to sulphoxybenzamides of general formula I
wherein
Z0 denotes a group selected from the formulae xe2x80x94X1xe2x80x94(CH2)rxe2x80x94X2xe2x80x94 and xe2x80x94CR4R5xe2x80x94,
A1 and A2 independently of one another each denote a 1,4-phenylene- or 1,3-phenylene group optionally substituted by one or more halogen atoms, C1-C8-alkyl groups, C2-C8-alkenyl groups, C1-C8-haloalkyl groups or C1-C8-alkoxy groups,
Z1 and Z2 independently of one another each denote a group of formula xe2x80x94X3xe2x80x94(CH2)sxe2x80x94X4xe2x80x94 or a single bond,
R1 denotes hydrogen, hydroxy, xe2x80x94COOxe2x80x94C1-C8-alkyl or xe2x80x94COOxe2x80x94C1-C4-alkyl-phenyl, whilst in the abovementioned group the phenyl ring in each case may be substituted by C1-C4-alkyl or C1-C4-alkoxy,
R2 and R3 independently of one another each denote a hydrogen or halogen atom, or a C1-C8-alkyl, C1-C8-haloalkyl, C1-C8-alkoxy, aryl, aryloxy or aralkyl group,
R4 and R5 independently of one another each denote hydrogen or C1-C4-alkyl,
X1 and X2 independently of one another each denote xe2x80x94O, xe2x80x94S, xe2x80x94NHxe2x80x94 or a single bond,
X3 and X4 independently of one another each denote xe2x80x94O, xe2x80x94S, xe2x80x94NHxe2x80x94 or a single bond,
m and n independently of one another each denote 0 or 1, and
r and s independently of one another denote an integer from 1 to 8,
optionally in the form of the tautomers, racemates, enantiomers, diastereomers and mixtures thereof, as well as optionally the pharmacologically acceptable salts thereof.
Preferred compounds are those of formula I wherein
Z0 denotes a group selected from the formulae xe2x80x94X1xe2x80x94(CH2)rxe2x80x94X2xe2x80x94 and xe2x80x94CR4R5xe2x80x94,
A1 and A2 independently of one another each denote a 1,4-phenylene or 1,3-phenylene group optionally substituted by a C1-C4-alkyl group or C2-C4-alkenyl group,
Z1 and Z2 independently of one another each denote a group of formula xe2x80x94X3xe2x80x94(CH2)sxe2x80x94X4xe2x80x94 or a single bond,
R1 denotes hydrogen,
R2 and R3 each denote a hydrogen atom,
R4 and R5 independently of one another each denote C1-C4-alkyl,
X1 and X2 independently of one another each denote xe2x80x94Oxe2x80x94 a single bond,
X3 and X4 independently of one another each denote xe2x80x94Oxe2x80x94 or a single bond,
m and n independently of one another each denote 0 or 1, and
r and s independently of one another each denote an integer from 1 to 3.
Another preferred embodiment comprises the compounds of formula I, wherein
Z0 denotes a group of formula xe2x80x94CR4R5xe2x80x94,
A1 and A2 independently of one another each denote a 1,4-phenylene or 1,3-phenylene group optionally substituted by a C1-C4-alkyl group or C2-C4-alkenyl group, and preferably A1 denotes 1,4-phenylene and A2 denotes 1,3-phenylene,
Z1 and Z2 independently of one another each denote a group of formula xe2x80x94X3xe2x80x94(CH2)sxe2x80x94X4xe2x80x94, and preferably Z1 denotes xe2x80x94Oxe2x80x94CH2xe2x80x94 and Z2 denotes xe2x80x94CH2xe2x80x94Oxe2x80x94
R1 denotes hydrogen,
R2 and R3 each denote a hydrogen atom,
R4 and R5 each denote methyl,
X3 and X4 independently of one another each denote xe2x80x94Oxe2x80x94 or a single bond,
m and n each denote 1, and
s denotes 1.
Also preferred are compounds of formula I wherein
Z0 denotes a group of formula xe2x80x94X1xe2x80x94(CH2)rxe2x80x94X2xe2x80x94,
A2 denotes a 1,4-phenylene group substituted by a C1-C4-alkyl group or C2-C4-alkenyl group, preferably a 1,4-phenylene group substituted by an n-propyl or allyl group,
Z2 denotes a single bond,
R1 denotes hydrogen,
R2and R3 each denote a hydrogen atom,
X1 and X2 independently of one another each denote xe2x80x94Oxe2x80x94,
m denotes 0,
n denotes 1, and
r denotes 2.
Unless specifically stated otherwise, the general definitions are used in the following sense: C1-C8-alkyl and C1-C4-alkyl generally denote a branched or unbranched hydrocarbon group with 1 to 4 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s), preferably flu orine, which may be identical to or different from one another. The following hydrocarbon groups are mentioned as examples:
methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups with 1 to 4 carbon atoms are preferred, such as methyl; ethyl, n-propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.
C2-C8-alkenyl and C2-C4-alkenyl generally denote a branched or unbranched unsaturated hydrocarbon group with 2 to 4 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s), preferably fluorine, which may be identical to or different from one another. The following hydrocarbon groups are mentioned as examples:
Vinyl, allyl, prop-1-enyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl. Unless otherwise stated, lower alkenyl groups with 2 to 4 carbon atoms, such as vinyl or allyl, are preferred.
The group xe2x80x94(CH2)rxe2x80x94 or xe2x80x94(CH2)sxe2x80x94 denotes a branched or unbranched double-bonded hydrocarbon bridge with 1 to 8 carbon atoms, which may optionally be substituted by one or more halogen atom(s), preferably fluorine, which may be identical to or different from one another.
Aryl generally denotes an aromatic group with 6 to 10 carbon atoms, preferably phenyl, while the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or. more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogenxe2x80x94such as fluorine, chlorine or brominexe2x80x94as well as hydroxyl.
Alkoxy generally denotes a straight-chain or branched hydrocarbon group with 1 to 8 carbon atom(s) bound via an oxygen atom. A lower alkoxy group with 1 to 3 carbon atom(s) is preferred. The methoxy group is particularly preferred.
Aryloxy generally denotes an aromatic group with 6 to 10 carbon atoms bound via an oxygen, preferably phenoxy, whilst the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogenxe2x80x94such as fluorine, chlorine or brominexe2x80x94as well as hydroxyl.
Aralkyl generally denotes a aromatic group with 6 to 10 carbon atoms bound via an alkylene group, preferably phenylalkyl, whilst the aromatic group may be substituted by one or more lower alkyl group(s), lower alkenyl group(s), trifluoromethyl group(s), cyano group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical or different; the preferred aryl group is an optionally substituted phenyl group, the preferred substituents being halogenxe2x80x94such as fluorine, chlorine or brominexe2x80x94as well as hydroxyl. The alkylene group is generally a double-bonded hydrocarbon bridge with 1 to 8 carbon atoms, preferably 1 to 3 carbon atoms, optionally substituted by one or more halogen atom(s)xe2x80x94preferably fluorinexe2x80x94which may be identical to or different from one another.
Most particularly preferred compounds are those of formulae IA and IB, 
The compounds IA and IB may be formed in vivo as metabolites of a corresponding LTB4-antagonistic compound with a free hydroxy group and exhibit the following Ki values in the receptor binding test:
As has been found, the compounds of formula I are characterised by their versatility of use in the therapeutic field. Particular emphasis should be laid on those applications for which the LTB4-receptor-antagonistic properties play a part.
The following should be mentioned in particular: arthritis, asthma, chronic obstructive lung diseases such as chronic bronchitis, psoriasis, ulcerative colitis, gastro- or enteropathy induced by nonsteroidal antiphlogistics, cystic or pulmonary fibrosis, Alzheimer""s disease, shock, reperfusion damage/ischaemia such as stroke or cardiac infarct, atherosclerosis, multiple sclerosis, autoimmune diseases, malignant neoplasia, alveolitis.
The new compounds may also be used to treat illnesses or conditions in which the passage of cells from the blood through the vascular endothelium into the tissues is of importance (such as metastasis) or illnesses and conditions in which the combination of LTB4 or another active substance (such as 12-HETE) with the LTB4 receptor has an influence on cell proliferation (e.g. chronic myeloid leukaemia).
The new compound may also be used in conjunction with other active substances, e.g. those which are used for the same indications, or e.g. with antiallergic agents, secretolytics, xcex22-adrenergics, steroids taken by inhalation, antihistamines, PDE4 inhibitors, peptido-leukotriene antagonists and/or PAF antagonists. They may be administered topically, orally, transdermally, nasally, parenterally or by inhalation.
The activity can be investigated pharmacologically and biochemically using tests as disclosed for example in WO 93/16036, pp. 15 to 17; reference is hereby made to the contents of this publication.
The therapeutic or prophylactic dose dependsxe2x80x94apart from the potency of the individual compounds and the patient""s body weightxe2x80x94on the nature and gravity of the condition. For oral administration the dosage is between 10 and 500 mg, preferably between 20 and 250 mg. By inhalation the amount of active substance delivered to the patient is between about 0.5 and 25, preferably between about 2 and 20 mg.
Solutions for inhalation generally contain between about 0.5 and 5% of active substance. The new compounds may be administered in conventional preparations, e.g. as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments and suppositories.